PharmacologyTier 1Medical Sciences concept

Diabetes drug mechanisms of action by class (sulfonylureas, biguanides, SGLT2i, DPP-4i, GLP-1, TZDs)

Core concept

Three questions separate the classes: does it need working beta cells, is insulin release glucose-dependent, and does it act on the kidney or the gut?

Insulin secretagogues - beta-cell dependent, glucose-INdependent

Sulfonylureas bind SUR1 on the beta-cell K-ATP channel -> channel closes -> depolarisation -> voltage-gated Ca influx -> insulin granule exocytosis
- Bypasses the glucose sensor entirely -> hypoglycaemia
Meglitinides - same channel, different site, shorter action

Incretin-based - beta-cell dependent, glucose-DEPENDENT

GLP-1 RA (semaglutide, dulaglutide, liraglutide) - inc glucose-dependent insulin, dec glucagon, dec gastric emptying, inc satiety
Tirzepatide - dual GIP/GLP-1 agonist, greater HbA1c and weight effect
DPP-4 inhibitors - block degradation of endogenous GLP-1/GIP; weaker, weight neutral

Insulin-independent

Metformin - inhibits mitochondrial complex I -> inc AMP:ATP -> AMPK activation -> dec hepatic gluconeogenesis, inc peripheral glucose uptake
SGLT2 inhibitors - block proximal tubular SGLT2 -> glycosuria, natriuresis, tubuloglomerular feedback
TZDs - PPAR-gamma agonists -> adipocyte differentiation, dec free fatty acids, inc insulin sensitivity
Acarbose - alpha-glucosidase inhibition at the brush border

Class	Hypo risk	Weight	CV/renal outcome
Metformin	No	Neutral/dec	Neutral-favourable
Sulfonylurea	Yes	inc	Neutral
SGLT2i	No	dec 2-3 kg	dec HF hospitalisation, dec CKD progression, dec CV death
GLP-1 RA	No	dec 4-6 kg	dec MACE, dec albuminuria
Tirzepatide	No	dec 8-12 kg	Favourable
DPP-4i	No	Neutral	Neutral (saxagliptin inc HF)
TZD	No	inc (fluid, fat)	dec stroke; inc HF, inc fracture, inc bladder cancer
Insulin	Yes	inc	Neutral

Hypoglycaemia only with agents that raise insulin independently of glucose - sulfonylureas, meglitinides, insulin
- Everything else causes hypoglycaemia only in combination with those
Metformin - lactic acidosis risk, withhold below eGFR 30, hold with contrast and acute illness; B12 deficiency on long-term use
SGLT2i - genital mycotic infection, volume depletion, euglycaemic DKA (withhold 3 days pre-surgery)
GLP-1 RA - nausea, delayed gastric emptying, gallstones, pancreatitis, medullary thyroid C-cell warning
Sulfonylurea hypoglycaemia is prolonged and recurrent - admit, dextrose infusion, octreotide if refractory

Comorbidity, not HbA1c, drives second-line choice
- Heart failure or CKD -> SGLT2 inhibitor
- Established ASCVD or obesity -> GLP-1 receptor agonist
- Cost-constrained -> sulfonylurea, accepting hypoglycaemia and weight gain
Metformin remains first-line with lifestyle in Australia; add the organ-protective agent regardless of whether HbA1c is at target in HF/CKD
Elderly, renal impairment, sulfonylurea -> the classic recurrent hypoglycaemia admission (glibenclamide worst; gliclazide preferred)
eGFR floors - metformin 30, most SGLT2i initiate to 20-25 for renal protection, GLP-1 RA safe in CKD
Insulin secretagogues fail as beta-cell function declines; incretins and insulin do not

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